New unique nanostructure to target drug-delivery treatment of cancer cells


Human BodyA unique nanostructure developed by a team of international researchers, including those at the University of Cincinnati, promises improved all-in-one detection, diagnoses and drug-delivery treatment of cancer cells.

 

The first-of-its-kind nanostructure is unusual because it can carry a variety of cancer-fighting materials on its double-sided (Janus) surface and within its porous interior. Because of its unique structure, the nano carrier can do all of the following:

  • Transport cancer-specific detection nanoparticles and biomarkers to a site within the body, e.g., the breast or the prostate. This promises earlier diagnosis than is possible with today’s tools.
  • Attach fluorescent marker materials to illuminate specific cancer cells, so that they are easier to locate and find for treatment, whether drug delivery or surgery.
  • Deliver anti-cancer drugs for pinpoint targeted treatment of cancer cells, which should result in few drug side effects. Currently, a cancer treatment like chemotherapy affects not only cancer cells but healthy cells as well, leading to serious and often debilitating side effects.

This research, titled “Dual Surface Functionalized Janus Nanocomposites of Polystyrene//Fe304@Si02 for Simultaneous Tumor Cell Targeting and pH-Triggered Drug Release,” will be presented as an invited talk on Oct. 30, 2013, at the annual Materials Science & Technology Conference in Montreal, Canada. Researchers are Feng Wang, a former UC doctoral student and now a postdoc at the University of Houston; Donglu Shi, professor of materials science and engineering at UC’s College of Engineering and Applied Science (CEAS); Yilong Wang of Tongji University, Shanghai, China; Giovanni Pauletti, UC associate professor of pharmacy; Juntao Wang of Tongji University, China; Jiaming Zhang of Stanford University; and Rodney Ewing of Stanford University.

This recently developed Janus nanostructure is unusual in that, normally, these super-small structures (that are much smaller than a single cell) have limited surface. This makes is difficult to carry multiple components, e.g., both cancer detection and drug-delivery materials. The Janus nanocomponent, on the other hand, has functionally and chemically distinct surfaces to allow it to carry multiple components in a single assembly and function in an intelligent manner.

“In this effort, we’re using existing basic nano systems, such as carbon nanotubes, graphene, iron oxides, silica, quantum dots and polymeric nano materials in order to create an all-in-one, multidimensional and stable nano carrier that will provide imaging, cell targeting, drug storage and intelligent, controlled drug release,” said UC’s Shi, adding that the nano carrier’s promise is currently greatest for cancers that are close to the body’s surface, such as breast and prostate cancer.

If such nano technology can someday become the norm for cancer detection, it promises earlier, faster and more accurate diagnosis at lower cost than today’s technology. (Currently, the most common methods used in cancer diagnosis are magnetic resonance imaging or MRI; Positron Emission Tomography or PET; and Computed Tomography or CT imaging, however, they are costly and time consuming to use.)

In addition, when it comes to drug delivery, nano technology like this Janus structure, would better control the drug dose, since that dose would be targeted to cancer cells. In this way, anticancer drugs could be used much more efficiently, which would, in turn, lower the total amount of drug administered.

Source: University of Cincinnati

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Smart Cancer Nanotheranostics


QD Solar Chip 2(Nanowerk Spotlight) Cancer is one of the leading  causes of death in the world and remains a difficult disease to treat. Current  problems associated with conventional cancer chemotherapies include insolubility  of drugs in aqueous medium; delivery of sub-therapeutic doses to target cells;  lack of bioavailability; and most importantly, non-specific toxicity to normal  tissues. Recent contributions of nanotechnology research address possible  solutions to these conundrums. Nevertheless, challenges remain with respect to  delivery to specific sites, real time tracking of the delivery system, and  control over the release system after the drug has been transported to the  target site.

Nanomedical research on nanoparticles is exploring these issues  and has already been showing potential solutions for cancer diagnosis and  treatment. But a heterogeneous disease like cancer requires smart approaches  where therapeutic and diagnostic platforms are integrated into a theranostic  approach.

Theranostics – a combination of the words therapeutics and diagnostics – describes a treatment platform that combines a  diagnostic test with targeted therapy based on the test results, i.e. a step  towards personalized medicine. Making use of nanotechnology materials and  applications, theranostic nanomedicine can be understood as an integrated  nanotherapeutic system, which can diagnose, deliver targeted therapy and monitor  the response to therapy.

Theranostic nanomedicine has the potential for simultaneous and  real time monitoring of drug delivery, trafficking of drug and therapeutic  responses.

Our Smart Materials and Biodevice group at the Biosensors and Bioelectronics Centre, Linkoping University,  Sweden, has demonstrated for the first time a MRI-visual order-disorder micellar nanostructures for smart  cancer theranostics.

        drug release mechanism via functional outcome of pH response The  drug release mechanism via functional outcome of the pH response illustrated in  the schematic diagram. (Image: Smart Materials and Biodevice group, Linköping  University)   In the report, we fabricated a novel pH-triggered tumour  microenvironment sensitive order-disorder nanomicelle platform for smart  theranostic nanomedicine.             

The real-time monitoring of drug distribution will help  physicians to assess the type and dosage of drug for each patient and thus will  prevent overdose that could result in detrimental side-effects, or suboptimal  dose that could lead to tumour progression.

Additionally, the monitoring of normal healthy tissues by  differentiating with the MRI contrast will help balance the estimation of lethal  dose (for normal tissue) and pharmacologically active doses (for tumour). As a  result, this will help to minimize off-target effects and enhance effective  treatment.

In the present report, the concurrent therapy by doxorubicin and  imaging strategies by superparamagnetic iron oxide nanoparticles with our smart  architecture will provide every detail and thus can enable stratification of  patients into categorized responder (high/medium/low), and has the potential to  enhance the clinical outcome of therapy.

It shows, for the first time, concentration dependent  T2-weighted MRI contrast for a monolayer of clustered cancer cells. The pH  tunable order-disorder transition of the core-shell structure induces the  relative changes in MRI that will be sensitive to tumour microenvironment and  stages.

     MRI visual order-disorder nanostructure for cancer nanomedicine A  novel MRI visual order-disorder nanostructure for cancer nanomedicine explores  pH-trigger mechanism for theranostics of tumour hallmark functions. The pH  tunable order-disorder transition induces the relative changes in MRI contrast.  The outcome elucidates the potential of this material for smart cancer  theranostics by delivering non-invasive real-time diagnosis, targeted therapy  and monitoring the course and response of the action. (Image: Smart Materials  and Biodevice group, Linköping University)

Our findings illustrate the potential of these biocompatible  smart theranostic micellar nanostructures as a nontoxic, tumour-target specific,  tumour-microenvironment sensitive, pH-responsive drug delivery system with  provision for early stage tumour sensing, tracking and therapy for cells  over-expressed with folate receptors. The outcomes elucidate the potential of  smart cancer theranostic nanomedicine in non-invasive real-time diagnosis,  targeted therapy and monitoring of the course and response of the action before,  during and after treatment regimen.

By Hirak K Patra, Nisar Ul Khali, Thobias Romu, Emilia  Wiechec, Magnus Borga, Anthony PF Turner and Ashutosh Tiwari, Biosensors and Bioelectronics Centre,  Linköping University, Sweden

Read more: http://www.nanowerk.com/spotlight/spotid=33186.php#ixzz2kTi8huZB

New theranostic nanoparticle delivers, tracks cancer drugs


201306047919620(Nanowerk News) University of New South Wales (UNSW)  chemical engineers have synthesised a new iron oxide nanoparticle that delivers  cancer drugs to cells while simultaneously monitoring the drug release in real  time.
The result, published online in the journal ACS Nano (“Using Fluorescence Lifetime Imaging Microscopy to  Monitor Theranostic Nanoparticle Uptake and Intracellular Doxorubicin  Release”), represents an important development for the emerging field of  theranostics – a term that refers to nanoparticles that can treat and diagnose  disease.
Iron oxide nanoparticles that can track drug delivery will  provide the possibility to adapt treatments for individual patients,” says  Associate Professor Cyrille Boyer from the UNSW School of Chemical Engineering.
By understanding how the cancer drug is released and its effect  on the cells and surrounding tissue, doctors can adjust doses to achieve the  best result.
Importantly, Boyer and his team demonstrated for the first time  the use of a technique called fluorescence lifetime imaging to monitor the drug  release inside a line of lung cancer cells.
“Usually, the drug release is determined using model experiments  on the lab bench, but not in the cells,” says Boyer. “This is significant as it  allows us to determine the kinetic movement of drug release in a true biological  environment.”
Magnetic iron oxide nanoparticles have been studied widely  because of their applications as contrast agents in magnetic resonance imaging,  or MRI. Several recent studies have explored the possibility of equipping these  contrast agents with drugs.
However, there are limited studies describing how to load  chemotherapy drugs onto the surface of magnetic iron oxide nanoparticles, and no  studies that have effectively proven that these drugs can be delivered inside  the cell. This has only been inferred.
With this latest study, the UNSW researchers engineered a new  way of loading the drugs onto the nanoparticle’s polymer surface, and  demonstrated for the first time that the particles are delivering their drug  inside the cells.
“This is very important because it shows that bench chemistry is  working inside the cells,” says Boyer. “The next step in the research is to move  to in-vivo applications.”
Source: University of New South Wales

Read more: http://www.nanowerk.com/news2/newsid=32972.php#ixzz2j9WI0HAR

Nanopolymers Open New Way to Detect Cancerous Tumors


201306047919620The drug which was synthesized in association with Control Laboratory of Food and Drug Department of Iran’s Ministry of Health, Hygiene, and Medical Education can be used in MRI as the contrast agents in addition to curing cancerous tumors.
The aim of this study was to evaluate the contrast optimization of silicon-based gadolinium oxide nanoparticles with nanocomposite coating, and to compare gadolinium nanoparticle with the common contrast agent in magnetic resonance imaging (Magnevist). In this study, the new emulsion made of gadolinium oxide nanoparticle and POSS-PCU nanocomposite was investigated. In comparison with Magnevist, gadolinium oxide nanoparticles can increase the signal of MRI by reducing relaxation time or by increasing the rate of relaxation.

They can also create high contrast optimization in MRI as positive contrast in comparison with iron oxide nanoparticles (negative contrast agent).
In line with targeting methods and through connecting to biocompatible materials, the new medicine has obtained other useful results in drug delivery in order to detect lymphatic glands of breast cancer and hepatic tumors.
Since the non-nanoic sample of this drug has acquired the confirmation of US Foodstuff and Medications Standard Organization, it has FDA certificate. The drug has passed the laboratorial and animal tests, and it is going to be tested on humans too.
Results of the research have been published in December 2010 in Biological Trace Element Research, vol. 137, issue 3. For more information about the details of the research, study the full article on pages 324-334 on the same journal.

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Future medicine: Stem cells can leverage silica nanoparticles to track where they actually go


QDOTS imagesCAKXSY1K 8Giving patients stem cells packaged with silica nanoparticles could help  doctors determine the effectiveness of the treatments by revealing where the  cells go after they’ve left the injection needle.

Researchers from Stanford University report in a paper  published on Wednesday in the journal Science Translational Medicine  that silica nanoparticles taken up by stem cells make the cells visible on  ultrasound imaging. While other imaging techniques such as MRI can show where  stem cells are located in the body, that method is not as fast, affordable, or  widely available as an ultrasound scanner, and more importantly, it does not  offer a real-time view of injection, say experts.

Stem cells have significant medical promise because they can be turned into  other types of living cell. As well as helping doctors adjust therapeutic  dosages in patients, the new technique could help scientists perfect stem cell  treatments, says senior author Sanjiv  Gambhir. “For the most part, researchers shoot blindly—they don’t quite know  where the cells are going when they are injected, they don’t know if they home  in to the right target tissue, they don’t know if they survive, and they don’t  know if they leak into other tissue types,” says Gambhir.

This, in part, could be slowing advances in stem cell treatments. “If stem  cells are going to be used as a legitimate medical treatment for the repair of  damaged or diseased tissue, then we will need to know precisely where they are  going so the treatments can be optimized,” says Lara  Bogart, a physicist at the University of Liverpool. Bogart is developing  magnetic nanoparticles for tracking stem cells using MRI.To get a better view of where cells are going during and after injection,  Gambhir and colleagues used nanoparticles made of silica, a material that  reflects sound waves, so it can be detected in an ultrasound scan. The  nanoparticles were incubated with mesenchymal stem cells, which can develop into  cell types including bone cells, fat cells, and heart cells. The cells ingested  the nanoparticles, which did not change the cells’ growth rate or ability to  develop into different cell types. Inside the cells, the nanoparticles clumped  together, which made them more visible in an ultrasound.

The researchers then injected the nanoparticle-laden stem cells into the  hearts of mice and tracked their movements. Many research groups are testing  stem cells as a treatment after a heart attack or for other heart conditions in  both lab animals (see “A  Step Toward Healing Broken Hearts with Stem Cells” and “Injecting  Stem Cells into the Heart Could Stop Chronic Chest Pain”) as well as in  patients in clinical trials. A fast and real-time imaging tool could help  because researchers and doctors need to be sure that the cells reach the most  beneficial spots in a sickly heart.

“It’s very important to know where you inject the cells because you don’t  want to put them in areas damaged by the heart attack; that tissue is dead and a  very hostile environment,” says Jeff Bulte, a cell engineer at the Johns Hopkins  University School of Medicine who was not involved in the study. “On the other  hand, you want to place them as close to the site of damage as possible,” he  says.

The silica nanoparticles can also be detected in MRI machines because they  contain a strongly magnetic heavy metal known as gadolinium that shows up in the  scans. And they can be detected optically (through microscopes) because they  carry a fluorescent dye. “This gives us three complementary ways to image the  same particle,” says Bogart. Depending on the part of the body receiving the  transplant, the type of scanner available and the amount of time since  injection, a researcher may choose one method over another.

The mice used in the study were healthy, but the team plans to test the  tracking method in mice or other lab animals that have heart damage. The team  will also use the nanoparticles in different cell types and do more toxicity  studies prior to filing for FDA approval to test the nanoparticles in humans. “It will be about a three-year process to do first-in-man studies,” says  Gambhir.

Read more: http://medcitynews.com/2013/03/future-medicine-stem-cells-can-leverage-silica-nanoparticles-to-track-cells-once-in-the-body/#ixzz2OXjcfbXH

stemcells

Nanoparticles for Molecular Imaging


by Professor Andrew Tsourkas

Professor Andrew Tsourkas, Cellular and Molecular Imaging LabDepartment of BioengineeringUniversity of Pennsylvania
Corresponding author: atsourk@seas.upenn.edu

Over the past decade there has been an explosion in the number of nanotechnology-based agents that have been applied to biological and medical applications. It is generally believed that these agents will revolutionize how medicine is practiced. One particularly promising direction that has garnered a great deal of interest is molecular imaging.

The development of nanotechnology-based imaging probes offers to substantially improve the specificity and sensitivity of diagnostic imaging by allowing for the non-invasive and quantitative detection of specific biomolecules in living subjects.

In general, molecular imaging probes consist of a nanoparticle that has been functionalized with a targeting agent. The targeting agent is typically selected to recognize a disease biomarker located on the cell surface;1-4 however, probes have also been developed that strictly bind healthy tissue, thus leaving malignancies within target tissues unlabeled.5-7 In either case, the nanoparticles serve to enhance the contrast between malignant and benign tissue.

Interest in the use of nanoparticles stems from their ability to provide improved contrast compared with more traditional contrast agents and the ability to control their pharmacokinetics through variations of their size, surface properties, and shape.8 The strong contrast enhancing capabilities of nanoparticles can typically be attributed to atomic constraints that occur at the nanometer size-scale and/or the cumulative effect that results from packing many contrast agents into nanometer-sized particles.

For example, when iron oxide particles are synthesized at the nanometer-size scale they exhibit “superparamagnetic” properties because they can exist as single-domain crystals. In contrast, larger iron oxide particles generally consist of multiple magnetic domains that are aligned in the short range, but at longer distances the domains are anti-aligned and thus exhibit a reduced net magnetic effect per iron ion.

As a result, on a per iron ion basis, nano-sized iron oxide particles are generally able to generate more contrast on magnetic resonance images than larger micron-sized nanoparticles. Of course, the total iron content cannot be ignored. Since, micron-sized iron oxide particles are composed of significantly more iron ions than nanoparticles, they exhibit much stronger MR contrast on a per particle basis. This has allowed single micron-sized particles to be imaged via MR.9

To date, most nanoparticles that have been developed for magnetic resonance imaging applications have been characterized in terms of their relaxivity per ion (e.g. Fe, Gd, etc). Although this is certainly of great value, it can be argued that for molecular imaging applications it is even more important to calculate relaxivity on a per particle basis. For example, if a tumor cell has ten receptors on its surface, the binding of ten micron-sized particles of iron oxide would certainly provide more contrast than ten nanoparticles, even though the smaller nanoparticles would likely have a higher relaxivity per iron ion than the micron-sized particle.

This argument is, of course, not limited to iron oxide particles. A recent comparison that we made between Gd-labeled dendrimers and Gd-labeled dendrimer nanoclusters (DNCs) also highlights the importance of calculating the relaxivity per nanoparticle.1 In this study, Gd-labeled DNCs were formed by simply cross-linking Gd-labeled dendrimers into a higher-order structure, with a mean hydrodynamic diameter of ~150nm. While both the dendrimers and DNCs exhibited a similar relaxivity per Gd ion, the DNCs possessed >1,000-times more Gd per particle. As a result of this higher payload, the tumor-targeted Gd-labeled DNCs provided a dramatic improvement in contrast compared with Gd-labeled dendrimers, in tumor-bearing mice.

Aside from the contrast-enhancing capabilities of molecular imaging agents, it is also of critical importance to characterize the pharmacokinetics of new nanoparticle formulations. Particle size, shape, and charge are all known to be major driving forces responsible for dictating the blood half-life and biodistribution.

In general, nanoparticles at the length scale of ~10-100nm have generally exhibited longer circulations times and improved tissue penetration than micron-sized particles. These pharmacokinetic properties can lead to improved targeting and in many cases can be used to overcome the lower contrast-enhancing capabilities of smaller particles – hence the growing interest in using nanoparticles as opposed to micron-sized particle for molecular imaging applications.

In applications where long circulation times and additional contrast is not necessary, there has even been a movement to make molecular imaging probes that are <5.5nm in diameter to encourage renal filtration.10 This would allow for more rapid imaging, since unbound nanoparticles would be cleared much faster, and reduced toxicity for the same reasons.

In addition to the physical-chemical properties of the nanoparticle itself, the targeting agent also plays an instrumental role in the utility of nanoparticle-based contrast agents. For the most part, targeting agents that have been evaluated for molecular imaging applications have mirrored those used for targeted therapeutics (e.g. folic acid, transferrin, anti-HER2/neu antibodies, etc.).

For cancer imaging, these agents have shown a great deal of promise when used to assess the availability of therapeutic targets and monitor the efficacy of treatment; however, tumor cell receptors are unlikely to be adopted for diagnostic imaging due to the lack of any single receptor that is highly up-regulated across most tumors.

For diagnostic imaging, a biomarker that is universally present would have to be identified for clinical utility. Borrowing from FDG-PET imaging, one option that is being explored involves taking advantage of the increased metabolic rate of cancer cells and the resultant acidic microenvironment. Accordingly, various agents are being developed that specifically bind to cells that exist in subphysiologic pH.11 Since, an acidic microenvironment is common to most tumors, it is expected that tumor pH could serve as a more universal target. Ligands that target angiogeneisis or hypoxia could also potentially be utilized to expand the versatility of targeted molecular imaging probes. Of course, when biomarkers with increased universality are selected, it often comes at the cost of reduced specificity – a criticism that has often plagued FDG-PET.

In conclusion, nanoparticles have shown great promise as molecular imaging probes. However, as the number of nanoparticle formulations continues to expand it will be increasingly important to establish proper indices by which they can be compared. It will also be important to develop creative targeting strategies that can be used to identify disease with high sensitivity and high predictive value.


References

1. Cheng Z, Thorek DL, Tsourkas A. Gadolinium-conjugated dendrimer nanoclusters as a tumor-targeted T1 magnetic resonance imaging contrast agent. Angew Chem Int Ed Engl. 2010;49(2):346-50.
2. Thorek DL, Chen AK, Czupryna J, Tsourkas A. Superparamagnetic iron oxide nanoparticle probes for molecular imaging. Ann Biomed Eng. 2006 Jan;34(1):23-38.
3. Tsourkas A, Shinde-Patil VR, Kelly KA, Patel P, Wolley A, Allport JR, Weissleder R. In vivo imaging of activated endothelium using an anti-VCAM-1 magnetooptical probe. Bioconjug Chem. 2005 May-Jun;16(3):576-81.
4. Zhang CY, Lu J, Tsourkas A. Iron chelator-based amplification strategy for improved targeting of transferrin receptor with SPIO. Cancer Biol Ther. 2008 Jun;7(6):889-95.
5. Montet X, Weissleder R, Josephson L. Imaging pancreatic cancer with a peptide-nanoparticle conjugate targeted to normal pancreas. Bioconjug Chem. 2006 Jul-Aug;17(4):905-11.
6. Reimer P, Weissleder R, Shen T, Knoefel WT, Brady TJ. Pancreatic receptors: initial feasibility studies with a targeted contrast agent for MR imaging. Radiology. 1994 Nov;193(2):527-31.
7. Tanimoto A, Kuribayashi S. Hepatocyte-targeted MR contrast agents: contrast enhanced detection of liver cancer in diffusely damaged liver. Magn Reson Med Sci. 2005;4(2):53-60.
8. Moghimi SM, Hamad I. Factors Controlling Pharmacokinetics of Intravenously Injected Nanoparticulate Systems. In: de Villiers MM, Aramwit P, Kwon GS, editors. Nanotechnology in Drug Delivery. New York: Springer; 2009. p. 267-82.
9. Shapiro EM, Skrtic S, Sharer K, Hill JM, Dunbar CE, Koretsky AP. MRI detection of single particles for cellular imaging. Proc Natl Acad Sci U S A. 2004 Jul 27;101(30):10901-6.
10. Choi HS, Liu W, Misra P, Tanaka E, Zimmer JP, Itty Ipe B, Bawendi MG, Frangioni JV. Renal clearance of quantum dots. Nat Biotechnol. 2007 Oct;25(10):1165-70.
11. Reshetnyak YK, Andreev OA, Lehnert U, Engelman DM. Translocation of molecules into cells by pH-dependent insertion of a transmembrane helix. Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6460-5.

Copyright AZoNano.com, Professor Andrew Tsourkas (University of Pennsylvania)

Nanotechnology and MRI imaging


October 17, 2012 by tildabarliya

Author: Tilda Barliya PhD via Pharmaceutical Intelligence: http://pharmaceuticalintelligence.com/2012/10/17/nanotechnology-and-mri-imaging/

The recent advances of “molecular and medical imaging” as an integrated discipline in academic medical centers has set the stage for an evolutionary leap in diagnostic imaging and therapy. Molecular imaging is not a substitute for the traditional process of image formation and interpretation, but is intended to improve diagnostic accuracy and sensitivity.

Medical imaging technologies allow for the rapid diagnosis and evaluation of a wide range of pathologies. In order to increase their sensitivity and utility, many imaging technologies such as CT and MRI rely on intravenously administered contrast agents. While the current generation of contrast agents has enabled rapid diagnosis, they still suffer from many undesirable drawbacks including a lack of tissue specificity and systemic toxicity issues. Through advances made in nanotechnology and materials science, researchers are now creating a new generation of contrast agents that overcome many of these challenges, and are capable of providing more sensitive and specific information (1)

Magnetic resonance imaging (MRI) contrast enhancement for molecular imaging takes advantage of superb and tunable magnetic properties of engineered magnetic nanoparticles, while a range of surface chemistry offered by nanoparticles provides multifunctional capabilities for image-directed drug delivery. In parallel with the fast growing research in nanotechnology and nanomedicine, the continuous advance of MRI technology and the rapid expansion of MRI applications in the clinical environment further promote the research in this area.

It is well known that magnetic nanoparticles, distributed in a magnetic field, create extremely large microscopic field gradients. These microscopic field gradients cause substantial diphase and shortening of longitudinal relaxation time (T1) and transverse relaxation time (T2 and T2*) of nearby nuclei, e.g., proton in the case of most MRI applications. The magnitudes of MRI contrast enhancement over clinically approved conventional gadolinium chelate contrast agents combined with functionalities of biomarker specific targeting enable the early detection of diseases at the molecular and cellular levels with engineered magnetic nanoparticles. While the effort in developing new engineered magnetic nanoparticles and constructs with new chemistry, synthesis, and functionalization approaches continues to grow, the importance of specific material designs and proper selection of imaging methods have been increasingly recognized (2)

Earlier investigations have shown that the MRI contrast enhancement by magnetic nanoparticles is highly related to their composition, size, surface properties, and the degree of aggregation in the biological environment.

Therefore, understanding the relationships between these intrinsic parameters and relaxivities of nuclei under influence of magnetic nanoparticles can provide critical information for predicting the properties of engineered magnetic nanoparticles and enhancing their performance in the MRI based theranostic applications. On the other hand, new contrast mechanisms and imaging strategies can be applied based on the novel properties of engineered magnetic nanoparticles. The most common MRI sequences, such as the spin echo (SE) or fast spin echo (FSE) imaging and gradient echo (GRE), have been widely used for imaging of magnetic nanoparticles due to their common availabilities on commercial MRI scanners. In order to minimize the artificial effect of contrast agents and provide a promising tool to quantify the amount of imaging probe and drug delivery vehicles in specific sites, some special MRI methods, such as  have been developed recently to take maximum advantage of engineered magnetic NPs

  • off-resonance saturation (ORS) imaging
  • ultrashort echo time (UTE) imaging

Because one of the major limitations of MRI is its relative low sensitivity, the strategies of combining MRI with other highly sensitive, but less anatomically informative imaging modalities such as positron emission tomography (PET) and NIRF imaging, are extensively investigated. The complementary strengths from different imaging methods can be realized by using engineered magnetic nanoparticles via surface modifications and functionalizations. In order to combine optical or nuclear with MR for multimodal imaging, optical dyes and radio-isotope labeled tracer molecules are conjugated onto the moiety of magnetic nanoparticles

Since most functionalities assembled by magnetic nanoparticles are accomplished by the surface modifications, the chemical and physical properties of nanoparticle surface as well as surface coating materials have considerable effects on the function and ability of MRI contrast enhancement of the nanoparticle core.

The longitudinal and transverse relaxivities, Ri (i=1, 2), defined as the relaxation rate per unit concentration (e.g., millimole per liter) of magnetic ions, reflects the efficiency of contrast enhancement by the magnetic nanoparticles as MRI contrast agents. In general, the relaxivities are determined, but not limited, by three key aspects of the magnetic nanoparticles:

  1. Chemical composition,
  2. Size of the particle or construct and the degree of their aggregation
  3. Surface properties that can be manipulated by the modification and functionalization.

(It is also recognized that the shape of the nanoparticles can affect the relaxivities and contrast enhancement. However these shaped particles typically have increased sizes, which may limit their in vivo applications. Nevertheless, these novel magnetic nanomaterials are increasingly attractive and currently under investigation for their applications in MRI and image-directed drug delivery).

Composition Effect: The composition of magnetic nanoparticles can significantly affect the contrast enhancing capability of nanoparticles because it dominates the magnetic moment at the atomic level. For instance, the magnetic moments of the iron oxide nanoparticles, mostly used nanoparticulate T2 weighted MRI contrast agents, can be changed by incorporating other metal ions into the iron oxide.  The composition of magnetic nanoparticles can significantly affect the contrast enhancing capability of nanoparticles because it dominates the magnetic moment at the atomic level. For instance, the magnetic moments of the iron oxide nanoparticles, mostly used nanoparticulate T2 weighted MRI contrast agents, can be changed by incorporating other metal ions into the iron oxide.

Size Effect: The dependence of relaxation rates on the particle size has been widely studied both theoretically and experimentally. Generally the accelerated diphase, often described by the R2* in magnetically inhomogeneous environment induced by magnetic nanoparticles, is predicted into two different regimes. For the relatively small nanoparticles, proton diffusion between particles is much faster than the resonance frequency shift. This resulted in the relative independence of T2 on echo time. The values for R2 and R2*are predicted to be identical. This process is called “motional averaging regime” (MAR). It has been well demonstrated that the saturation magnetization Ms increases with the particle size. A linear relationship is predicted between Ms1/3 and d-1. Therefore, the capability of MRI signal enhancement by nanoparticles correlates directly with the particle size. 

Surface Effect: MRI contrast comes from the signal difference between water molecules residing in different environments that are under the effect of magnetic nanoparticles. Because the interactions between water and the magnetic nanoparticles occur primarily on the surface of the nanoparticles, surface properties of magnetic nanoparticles play important roles in their magnetic properties and the efficiency of MRI contrast enhancement. As most biocompatible magnetic nanoparticles developed for in vivo applications need to be stabilized and functionalized with coating materials, the coating moieties can affect the relaxation of water molecules in various forms, such as diffusion, hydration and hydrogen binding.

The early investigation carried at by Duan et al suggested that hydrophilic surface coating contributes greatly to the resulted MRI contrast effect. Their study examined the proton relaxivities of iron oxide nanocrystals coated by copolymers with different levels of hydrophilicity including: poly(maleic acid) and octadecene (PMO), poly(ethylene glycol) grated polyethylenimine (PEG-g-PEI), and hyperbranched polyethylenimine (PEI). It was found that proton relaxivities of those IONPs depend on the surface hydrophilicity and coating thickness in addition to the coordination chemistry of inner capping ligands and the particle size.

The thickness of surface coating materials also contributed to the relaxivity and contrast effect of the magnetic nanoparticles. Generally, the measured T2 relaxation time increases as molecular weight of PEG increases.

In Summary

Much progress has taken place in the theranostic applications of engineered magnetic nanoparticles, especially in MR imaging technologies and nanomaterials development. As the feasibilities of magnetic nanoparticles for molecular imaging and drug delivery have been demonstrated by a great number of studies in the past decade, MRI guiding and monitoring techniques are desired to improve the disease specific diagnosis and efficacy of therapeutics. Continuous effort and development are expected to be focused on further improvement of the sensitivity and quantifications of magnetic nanoparticles in vivo for theranostics in future.

The new design and preparation of magnetic nanoparticles need to carefully consider the parameters determining the relaxivities of the nanoconstructs. Sensitive and reliable MRI methods have to be established for the quantitative detection of magnetic nanoparticles. The new generations of magnetic nanoparticles will be made not only based on the new chemistry and biological applications, but also with combined knowledge of contrast mechanisms and MRI technologies and capabilities. As new magnetic nanoparticles are available for theranostic applications, it is anticipated that new contrast mechanism and MR imaging strategies can be developed based on the novel properties of engineered magnetic nanoparticles.

References:

1http://www.omicsonline.org/2157-7439/2157-7439-2-115.php

2http://www.clinical-mri.com/pdf/CMRI/8036XXP14Ap454-472.PDF

3http://www.thno.org/v02p0086.htm

4http://www.omicsonline.org/2157-7439/2157-7439-2-115.pdf

5http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3017480/

6http://www.nature.com/nmeth/journal/v7/n12/full/nmeth1210-957.html

7http://endomagnetics.com/wp-content/uploads/2011/01/TargOncol_Review_2009.pdf

8http://www.nature.com/nnano/journal/v2/n5/abs/nnano.2007.105.html

9http://www.azonano.com/article.aspx?ArticleID=2680